Facile skin targeting of a thalidomide analog containing benzyl chloride moiety alleviates experimental psoriasis via the suppression of MAPK/NF-κB/AP-1 phosphorylation in keratinocytes.

Abstract

BACKGROUND:

Thalidomide can be a TNF-α inhibitor for treating skin inflammation. This drug exhibits a strong toxicity that limits its application.

OBJECTIVE:

We synthesized a thalidomide analog containing the benzyl chloride group (2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione, CDI) to examine anti-inflammatory activity against psoriasis.

METHODS:

The evaluation was conducted by the experimental platforms of in vitro TNF-α- or imiquimod (IMQ)-stimulated HaCaT cells and in vivo IMQ-induced psoriasiform plaque.

RESULTS:

Using the in vitro keratinocyte model, we demonstrated a greater inhibition of IL-1β, IL-6, and IL-24 by CDI than by thalidomide. No significant cytotoxicity was observed at 100 μM. CDI delivered facilely into the skin with a cutaneous targeting ability 228-fold greater than thalidomide. CDI caused a negligible irritation on healthy mouse skin. We showed that topically applied CDI reduced IMQ-induced red scaly lesions, hyperplasia, microabscesses, and cytokine expression in the mouse model. The skin-barrier function measured by transepidermal water loss (TEWL) could be partially recovered from 50.6-36.3 g/m2/h by CDI. The mechanistic study showed that CDI suppressed cytokine production by inhibiting the phosphorylation of NF-κB and AP-1 via MAPK pathways.

CONCLUSION:

CDI would be beneficial for the development of a therapeutic agent against psoriasis.

• Authors: Kai-Wei Tang, Zih-Chan Lin, Pei-Wen Wang, Ahmed Alalaiwe, Chih-Hua Tseng, Jia-You Fang
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 99 Issue 2 Pg. 90-99 (Aug 2020) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 32622642 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• NF-kappa B
• TNF protein, human
• Tnf protein, mouse
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• Thalidomide
• Imiquimod

Topics

• Administration, Cutaneous
• Animals
• Disease Models, Animal
• HaCaT Cells
• Humans
• Imiquimod (administration & dosage, immunology)
• Keratinocytes (drug effects, immunology, metabolism)
• MAP Kinase Signaling System (drug effects, immunology)
• Male
• Mice
• NF-kappa B (metabolism)
• Phosphorylation (drug effects, immunology)
• Psoriasis (drug therapy, immunology, pathology)
• Skin (drug effects, immunology, pathology)
• Thalidomide (analogs & derivatives, pharmacology, therapeutic use)
• Transcription Factor AP-1 (metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology, metabolism)